The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals.

Abstract

Insulin resistance leads to hypertriglyceridemia and hepatic steatosis and is associated with increased SREBP-1c, a transcription factor that activates fatty acid synthesis. Here, we show that steatosis in insulin-resistant ob/ob mice was abolished by deletion of Scap, an escort protein necessary for generating nuclear isoforms of all three SREBPs. Scap deletion reduced lipid synthesis and prevented fatty livers despite persistent obesity, hyperinsulinemia, and hyperglycemia. Scap deficiency also prevented steatosis in mice fed high-fat diets. Steatosis was also prevented when siRNAs were used to silence Scap in livers of sucrose-fed hamsters, a model of diet-induced steatosis and hypertriglyceridemia. This silencing reduced all three nuclear SREBPs, decreasing lipid biosynthesis and abolishing sucrose-induced hypertriglyceridemia. These results demonstrate that SREBP activation is essential for development of diabetic hepatic steatosis and carbohydrate-induced hypertriglyceridemia, but not insulin resistance. Inhibition of SREBP activation has therapeutic potential for treatment of hypertriglyceridemia and fatty liver disease.

• Authors: Young-Ah Moon, Guosheng Liang, Xuefen Xie, Maria Frank-Kamenetsky, Kevin Fitzgerald, Victor Koteliansky, Michael S Brown, Joseph L Goldstein, Jay D Horton
• Journal: Cell metabolism (Cell Metab) Vol. 15 Issue 2 Pg. 240-6 (Feb 08 2012) ISSN: 1932-7420 [Electronic] United States
• PMID: 22326225 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• DNA Primers
• Intracellular Signaling Peptides and Proteins
• Lipids
• Membrane Proteins
• SREBP cleavage-activating protein
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• siroamide
• Heme

Topics

• Animals
• Cricetinae
• DNA Primers (genetics)
• Fatty Liver (genetics, metabolism)
• Gene Silencing
• Heme (analogs & derivatives)
• Hypertriglyceridemia (metabolism)
• Immunoblotting
• Intracellular Signaling Peptides and Proteins (deficiency, genetics, metabolism)
• Lipids (biosynthesis)
• Membrane Proteins (deficiency, genetics, metabolism)
• Mice
• Mice, Transgenic
• RNA Interference
• Real-Time Polymerase Chain Reaction
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)